Alimta

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Requirement for Premedication and Concomitant Medication
to Reduce Toxicity

Vitamin Supplementation

Prior to treatment with ALIMTA, initiate supplementation
with oral folic acid and intramuscular vitamin B12 to reduce the severity of
hematologic and gastrointestinal toxicity of ALIMTA [see DOSAGE AND ADMINISTRATION].
Do not substitute oral vitamin B12 for intramuscular vitamin B12. In clinical
studies, the incidence of the following Grade 3-4 toxicities were higher in
patients with mesothelioma who were never supplemented as compared to patients
who were fully supplemented with folic acid and vitamin B12 prior to and
throughout ALIMTA treatment: neutropenia [38% versus 23%], thrombocytopenia [9%
versus 5%], febrile neutropenia [9% versus 0.6%], and infection with neutropenia
[6% versus. 0].

Corticosteroids

Administer dexamethasone the day before, the day of, and
the day after ALIMTA administration [see DOSAGE AND ADMINISTRATION].

Decreased Renal Function

ALIMTA is primarily eliminated unchanged by renal
excretion. No dosage adjustment is needed in patients with creatinine clearance
≥ 45 mL/min. Insufficient numbers of patients have been studied with
creatinine clearance < 45 mL/min to give a dose recommendation. Therefore,
ALIMTA should not be administered to patients whose creatinine clearance is
< 45 mL/min [see DOSAGE AND ADMINISTRATION].

One patient with severe renal impairment (creatinine
clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of
drug-related toxicity following administration of ALIMTA alone.

Use with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
with Mild to Moderate Renal Insufficiency

Caution should be used when administering NSAIDs
concurrently with ALIMTA to patients with mild to moderate renal insufficiency
(creatinine clearance from 45 to 79 mL/min) [see DRUG INTERACTIONS].

Required Laboratory Monitoring

Obtain a complete blood count and renal function tests at
the beginning of each cycle and as needed. Do not initiate a cycle of treatment
unless the ANC is ≥ 1500 cells/mm³, the platelet count is
≥ 100,000 cells/mm³, and creatinine clearance is ≥ 45
mL/min [see DOSAGE AND ADMINISTRATION].

Pregnancy Category D

Based on its mechanism of action, ALIMTA can cause fetal
harm when administered to a pregnant woman. Pemetrexed administered
intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and
teratogenic in mice at greater than 1/833rd the recommended human dose. If
ALIMTA is used during pregnancy, or if the patient becomes pregnant while
taking this drug, the patient should be apprised of the potential hazard to the
fetus. Women of childbearing potential should be advised to avoid becoming
pregnant. Women should be advised to use effective contraceptive measures to
prevent pregnancy during treatment with ALIMTA [see Use in Specific
Populations].

Patient Counseling Information

Instruct patients on the need for folic acid and vitamin
B12 supplementation to reduce treatment-related hematologic and
gastrointestinal toxicity and of the need for corticosteroids to reduce
treatment-related dermatologic toxicity [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Inform patients of the risk of low blood cell counts and
instruct them to immediately contact their physician for signs of infection,
including fever, bleeding or symptoms of anemia.

Instruct patients to contact their physician if
persistent vomiting, diarrhea, or signs of dehydration appear.

Instruct patients to inform their physician of all
concomitant prescription or over-the-counter medications they are taking,
particularly those for pain or inflammation such as non-steroidal
anti-inflammatory drugs [see DRUG INTERACTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity studies have been conducted with
pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in
mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay,
CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or
greater to male mice (about 1/1666 the recommended human dose on a mg/m² basis)
resulted in reduced fertility, hypospermia, and testicular atrophy.

Use In Specific Populations

Pregnancy

Teratogenic Effects - Pregnancy Category D

[see WARNINGS AND
PRECAUTIONS]

Based on its mechanism of action, ALIMTA can cause fetal
harm when administered to a pregnant woman. There are no adequate and well
controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic,
fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of
pemetrexed when given during organogenesis caused fetal malformations
(incomplete ossification of talus and skull bone; about 1/833rd the recommended
intravenous human dose on a mg/m² basis), and cleft palate (1/33rd
the recommended intravenous human dose on a mg/m² basis).
Embryotoxicity was characterized by increased embryo-fetal deaths and reduced
litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes
pregnant while taking this drug, the patient should be apprised of the
potential hazard to the fetus. Women of childbearing potential should be
advised to use effective contraceptive measures to prevent pregnancy during the
treatment with ALIMTA.

Nursing Mothers

It is not known whether ALIMTA or its metabolites are
excreted in human milk. Because many drugs are excreted in human milk, and
because of the potential for serious adverse reactions in nursing infants from
ALIMTA, a decision should be made to discontinue nursing or discontinue the
drug, taking into account the importance of the drug for the mother.

Pediatric Use

Efficacy of ALIMTA in pediatric patients has not been
demonstrated. ALIMTA was administered as an intravenous infusion over 10
minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid
tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All
patients received pretreatment with vitamin B12 and folic acid supplementation
and dexamethasone. The dose escalation in the Phase 1 study determined the
maximum tolerated dose was 1910 mg/m² and this dose (or 60 mg/kg for
patients < 12 months old) was evaluated in the Phase 2 study of patients with
relapsed or refractoryosteosarcoma, Ewing sarcoma/peripheral PNET,
rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial
PNET, or non-brainstem high grade glioma. No responses were observed among the
72 patients in this Phase 2 trial. The most common toxicities reported were
hematological (leukopenia, neutropenia/granulocytopenia, anemia,
thrombocytopenia, and lymphopenia), liver function abnormalities (increased
ALT/AST), fatigue, and nausea.

The single dose pharmacokinetics of ALIMTA administered
in doses ranging from 400 to 2480 mg/m² were evaluated in the Phase
1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age
12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase
proportionally with dose. The average pemetrexed clearance (2.30 L/h/m²)
and half-life (2.3 hours) in pediatric patients were comparable to values
reported in adults.

Geriatric Use

ALIMTA is known to be substantially excreted by the
kidney, and the risk of adverse reactions to this drug may be greater in
patients with impaired renal function. Renal function monitoring is recommended
with administration of ALIMTA. No dose reductions other than those recommended
for all patients are necessary for patients 65 years of age or older [see DOSAGE
AND ADMINISTRATION].

Of 3,946 patients (34.0% ≥ 65) studied across the
five clinical trials [see Clinical Studies], the effect of ALIMTA on
survival was similar in patients < 65 compared to ≥ 65 years of age.
There were no differences in safety with the exception of the following Grade
3-4 adverse reactions, which were noted in at least one of the five trials to
be greater in patients 65 years of age and older as compared to younger
patients: anemia, fatigue, thrombocytopenia, hypertension, and neutropenia.

Patients with Hepatic Impairment

There was no effect of elevated AST, ALT, or total
bilirubin on the pharmacokinetics of pemetrexed. However, no formal studies
have been conducted to examine the pharmacokinetics of pemetrexed in patients
with hepatic impairment [see CLINICAL PHARMACOLOGY].

Patients with Renal Impairment

ALIMTA is known to be primarily excreted by the kidneys.
Decreased renal function will result in reduced clearance and greater exposure
(AUC) to ALIMTA compared with patients with normal renal function [see DOSAGE
AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Cisplatin
coadministration with ALIMTA has not been studied in patients with moderate
renal impairment.

Gender

Of 3,946 patients (Male 70.5%) studied across the five
registration studies for ALIMTA indications [see Clinical Studies], the
effect of ALIMTA on survival was similar in female and male patients.

Race

Of 3,946 patients (Caucasian 78.6%) studied across the
five registration studies for ALIMTA indications [see Clinical Studies],
the effect of ALIMTA on survival was similar in the Caucasian and non-Caucasian
patients.

Last reviewed on RxList: 9/27/2013
This monograph has been modified to include the generic and brand name in many instances.